Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity

Fader, Kelly A.; Nault, Rance; Kirby, Mathew P.; Markous, Gena; Matthews, Jason; Zacharewski, Timothy R.

doi:10.1016/j.taap.2017.02.006

Cited by 47 publications

(103 citation statements)

References 64 publications

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“…It is generally recognized that iron overload is connected with hepatic inflammation through ROS [21-23]. In the present study, we show that elimination of oxidative stress by the antioxidant Vit.E cannot remove IO-induced hepatic inflammation.…”

Section: Discussionsupporting

confidence: 72%

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

Tang¹,

Jia²,

Niu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Iron overload (IO) is accompanied by hepatic inflammation. The chemokine (C-C motif) ligand 2 (CCL2) mediates inflammation, and its overexpression is associated with IO. However, whether IO results in CCL2 overexpression in the liver and the underlying mechanisms are unclear. Methods: We subjected mice to IO by administering intraperitoneal injections of dextran-iron or by feeding mice a 3% dextran-iron diet to observe the effects of IO on miR-122/CCL2 expression through real-time qPCR and Western blot analysis. We also used indicators, including the expression of the inflammatory cytokine, the inflammation score based on H&E staining and the serum content of ALT and AST to evaluate the effects of IO on hepatic inflammation. Meanwhile, we observed the effects of vitamin E on IO-induced hepatic inflammation. In cells, we used 100 µΜ FeSO₄ or 30 µΜ Holo-Tf to produce IO and observed the roles of miR-122 in regulating CCL2 expression by using miR-122 mimics or inhibitors to overexpress or inhibit miR-122. Then, we used a dual-luciferase reporter assay to prove that miR-122 regulates CCL2 expression through direct binding to its complementary sequence in the CCL2 mRNA 3’UTR. Results: IO induces the downregulation of miR-122 and the upregulation of CCL2, as well as inflammatory responses both in vitro and in vivo. Although IO-induced oxidative stress is eliminated by the antioxidant vitamin E, IO-induced hepatic inflammation still exists, which probably can be explained by the fact that vitamin E has no effects on the miR-122/CCL2 pathway. In in vitro experiments, the overexpression and inhibition of miR-122 significantly reduced and increased CCL2 expression, respectively. The dual-luciferase reporter assay indicates that miR-122 binds CCL2 mRNA 3’UTR. Conclusion: We propose the roles of miR-122/CCL2 in IO-induced hepatic inflammation. Our studies should provide a new clue for developing clinical strategies for patients with IO.

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Section: Discussionsupporting

confidence: 72%

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

Tang¹,

Jia²,

Niu³

et al. 2017

Cell Physiol Biochem

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“…More recently, duodenal epithelial and hepatic RNA-Seq analyses identified TCDD-elicited changes in gene expression consistent with iron overloading. Specifically, TCDD caused the dose-dependent repression of hepcidin, the master regulator of systemic iron homeostasis, resulting in a 2.6-fold increase in serum iron with accumulating levels spilling into urine [28]. Iron lies at the cross-section of multiple pathways associated with TCDD-elicited toxicity.…”

Section: Beyond Gene Expression – An Integrated Systems Approachmentioning

confidence: 99%

“…Free heme not only oxidizes biological macromolecules including proteins, DNA, and lipids, but also contributes to inflammation. Concomitantly, TCDD represses downstream enzymes involved in heme biosynthesis including uroporphyrinogen decarboxylase ( Urod ), which catalyzes the conversion of uroporphyrinogen III to coproporphyrinogen III [28]. Interestingly, human porphyria cutanea tarda (PCT), a photosensitive skin disease involving the overproduction of hepatic porphyrins, is the result of insufficient UROD activity.…”

Section: Beyond Gene Expression – An Integrated Systems Approachmentioning

confidence: 99%

“…Uroporphyrin III is not a substrate for heme synthesis and thus accumulates in the liver, skin, and urine [31]. Accordingly, TCDD increases total urinary porphyrin levels with collected urine exhibiting a dark tea color indicative of PCT [28]. Fe deficiency has been shown to completely protect against TCDD-elicited porphyria in mice [32,33] while Fe supplementation exacerbates toxicity [34].…”

Section: Beyond Gene Expression – An Integrated Systems Approachmentioning

confidence: 99%

“…TCDD-elicited heme accumulation promotes the induction of heme oxygenase 1 ( Hmox1 ) through the release of BACH1-mediated repression [28]. Although Hmox1 -catalyzed catabolism of heme to bilirubin, carbon monoxide (CO), and iron reduces free heme-elicited toxicity, this reaction contributes to the free iron pool and thus promotes TCDD-elicited oxidative stress.…”

Section: Beyond Gene Expression – An Integrated Systems Approachmentioning

confidence: 99%

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Beyond the aryl hydrocarbon receptor: Pathway interactions in the hepatotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds

Fader

Zacharewski

2017

Current Opinion in Toxicology

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the prototypical ligand for a group of environmental halogenated aromatic hydrocarbon contaminants which elicit hepatotoxicity and other toxic responses through activation of the aryl hydrocarbon receptor (AhR). Despite the conservation of the AhR and its signaling pathway, TCDD-elicited differential gene expression networks are species-specific, consistent with differences in sensitivity and toxic responses between species. This review integrates gene expression studies with complementary phenotypic analyses (e.g., metabolomics, clinical biochemistry, and histopathology) to elucidate the pathways through which TCDD and related compounds cause hepatotoxicity beyond AhR activation. We propose that AhR-mediated toxicity is a collective response to the cumulative burden of metabolic reprogramming across multiple pathways. Consequently, nutrition, health status, and genetic background establish the basis for differences in sensitivity and predisposition to adverse outcomes between species, sub-populations, tissues, and cells.

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A Negative Feedback Loop and Transcription Factor Cooperation Regulate Zonal Gene Induction by 2, 3, 7, 8‐Tetrachlorodibenzo‐p‐Dioxin in the Mouse Liver

2021

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The cytochrome P450 (Cyp) proteins Cyp1A1 and Cyp1A2 are strongly induced in the mouse liver by the potent environmental toxicant 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin (TCDD), acting through the aryl hydrocarbon receptor (AHR). The induction of Cyp1A1 is localized within the centrilobular regions of the mouse liver at low doses of TCDD, progressing to pan‐lobular induction at higher doses. Even without chemical perturbation, metabolic functions and associated genes are basally zonated in the liver lobule along the central‐to‐portal axis. To investigate the mechanistic basis of spatially restricted gene induction by TCDD, we have developed a multiscale computational model of the mouse liver lobule with single‐cell resolution. The spatial location of individual hepatocytes in the model was calibrated from previously published high‐resolution images. A systems biology model of the network of biochemical signaling pathways underlying Cyp1A1 and Cyp1A2 induction was then incorporated into each hepatocyte in the model. Model simulations showed that a negative feedback loop formed by binding of the induced Cyp1A2 protein to TCDD, together with cooperative gene induction by the β‐catenin/AHR/TCDD transcription factor complex and β‐catenin, help produce the spatially localized induction pattern of Cyp1A1. Although endogenous WNT regulates the metabolic zonation of many genes, it was not a driver of zonal Cyp1A1 induction in our model. Conclusion: In this work, we used data‐driven computational modeling to identify the mechanistic basis of zonally restricted gene expression induced by the potent and persistent environmental pollutant TCDD. The multiscale model and derived results clarify the mechanisms of dose‐dependent hepatic gene induction responses to TCDD. Additionally, this work contributes to our broader understanding of spatial gene regulation along the liver lobule.

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Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity

Cited by 47 publications

References 64 publications

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

Beyond the aryl hydrocarbon receptor: Pathway interactions in the hepatotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds

A Negative Feedback Loop and Transcription Factor Cooperation Regulate Zonal Gene Induction by 2, 3, 7, 8‐Tetrachlorodibenzo‐p‐Dioxin in the Mouse Liver

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